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Insertional Mutagenesis of the Human Genome
Genome Evolution: ]] The genome of an organism is defined as “an organism’s complete set of DNA, including all of its genes”3. Genomes are in no way static, in fact, they are ever changing due to two basic mechanisms: by duplicating the genes already within the genome or by acquiring new genes from other species2. Horizontal gene transfer (or lateral gene transfer) is the main way that prokaryotes acquire new genes within their genomes. There are three basic mechanisms for exchanging DNA material: transformation, transduction, and conjugation. Transformation is the uptake of naked DNA by a cell, which is then incorporated within its genome4. Transduction is the process by which DNA material is transferred from one bacterium to another through the use of a virus4. Finally, conjugation is the uptake of DNA material by direct cell-to-cell contact4. All of these events predominantly occur within bacteria, but another whole aspect of genome evolution is the alteration of the human genome by a few different processes such as: mitochondrial insertions, the use of mobile elements, and viral integrations. These events are being more widely studied today and may lead to the understanding of many diseases and the genetic causes associated with them. Mitochondrial Insertions: Mitochondrial insertions, in a nutshell, are when mitochondrial DNA exits the mitochondria and gets incorporated within the nuclear genome of a human cell. The mitochondrial DNA (mtDNA) that gets transferred is called a nuclear mitochondrial DNA segment (numts). Scientists aren’t completely sure how this process works yet but they believe it occurs due to four different processes: mitochondrial lysis, degradation of abnormal mitochondria, direct nuclear-mitochondrial contact, or mitochondrial DNA encapsulation inside the nucleus1. No matter the method, however, the mtDNA is then incorporated into the nuclear genome by non-homologous end jointing of double strand break repair, and then may cause effects within the cell. Although it is not understood if these insertions cause disease states within humans, there are a few examples that suggest they do. There are some fairly rare occurrences where mtDNA insertion in the nuclear genome of human cells is associated with disease states1: * A 41bp insertion of mtDNA causes a translocation between chromosome 9 and 11. * A 251bp numt insertion into the human plasma factor VII gene causes a severe deficiency in factor VII. * A 72bp numt insertion into the GLI3 gene is associated with Pallister-Hall syndrome. * A 93bp numt insertion into MCOLN1. * A 36bp numt insertion into the USH1C gene is implicated with Usher Syndrome. Other observations of somatic numts are associated with aging within rates and an increase in environmental stress within plants1. Further study of mtDNA insertion into human nuclear genomes could lead to a better understanding of genetic causes for certain diseases. Mobile Elements: ]] Very similar to the idea of horizontal gene transfer within bacteria, the movement of mobile elements throughout human genomes can have an effect on the overall structure and functioning of human genes and may even lead to diseases. The two main mobile elements known today are the LINE-1 (L1) and Alu elements. These two mobile elements move throughout the human genome through germ line retro transposition and upon reactivation may lead to tumor genesis1. L1 has been largely associated with both colon and breast cancers, as highlighted by the following examples: * L1 insertion in APC gene in colon tumor, but NOT normal colon cell. * Colorectal tumor had L1 insertions that were not within the normal DNA. * Within lung cancer tumors, 30% had 1-3 L1 insertions1. There are over 1 million Alu insertions present within the human genome and it also has some cancerous associations such as: * Insertions in MLV12 and MLL genes associated with leukemia. * Insertions in BRCA1 and BRCA2 genes associated with breast cancer. * Insertions in MLH1 and MSH2 genes associated with colorectal cancer syndrome1. Although it is not clear if these mobile element insertions into the human genome have cancerous effects on human cells, the high number of them within cancerous cells suggest a strong link between the two. Viral Integrations: The last type of genomic alteration is viral integrations, which are when viruses get into the human genome and insert their DNA into the human genome. This process is also associated with cancer because the inserted viral DNA alters the somatic human genome and causes dysfunction. In 2008, 15-20% of all cancers were linked to infection with a virus, parasite, or bacteria1. When a virus inserts its DNA into the human genome, it results in the loss of E1 and E2 proteins and the deregulation of E6 protein, which leads to the down regulation of the p53 pathway. The p53 pathway is responsible for cell apoptosis, so this down regulation causes cells to proliferate uncontrollably and promotes tumor formation. Some examples of viral integration into the human genome are: * 80-100% of human papillomavirus (HPV) integrations involve HPV16/18 and lead to cervical cancer. * Numerous hepatitis B virus (HBV) integrations within common oncogenes such as TERT, ITPR1, IRAK2, MAPK1, MLL2, MLL4, and CCNE1. * HBV integrations associated with hepatocellular carcinoma. * The level of HBV integrations can be used to predict patient survival (>3 insertions associated with low survival, <3 insertions associated with high survival)1. Once we understand the scope of viral integrations within the human genome, we can begin to further understand how alterations within the human genome can lead to cancers. Resources: # A Review of Bacteria-Animal Lateral Gene Transfer May Inform Our Understanding of Diseases like Cancer by Kelly Robinson, Karsten Sieber, and Julie Hotopp # How Genomes Evolve at http://www.ncbi.nlm.nih.gov/books/NBK21112/ # What Is A Genome? at http://ghr.nlm.nih.gov/handbook/hgp/genome # Wikipedia.org